Cdk2 suppresses cellular senescence induced by the c-myc oncogene
Cdk2 suppresses cellular senescence induced by the c-myc oncogene
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DOI：
10.1038/ncb2004
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发表时间：
2010-01-01
影响因子：
21.3
通讯作者：
Amati, Bruno
中科院分区：
文献类型：
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作者：
Campaner, Stefano;Doni, Mirko;Amati, Bruno
激活的癌基因诱导代偿性肿瘤抑制反应，如细胞衰老或凋亡，但决定主要结果的信号仍有待充分理解（1，2）。在这里，我们揭示了Cdk 2（细胞周期蛋白依赖性激酶2）在抑制Myc诱导的衰老中的作用。Myc的短期激活促进了野生型或Cdk 2敲除（4，5）小鼠胚胎成纤维细胞（MEF）中的细胞周期进程（3）。然而，在敲除MEFs中，最初的过度增殖反应之后是细胞衰老。Cdk 2的丢失也引起体内胰腺β细胞或脾B细胞对Myc诱导的衰老的敏感性，与后者中延迟的淋巴瘤发作相关。Cdk 2（-/-）MEFs也在异位Wnt信号传导或在没有致癌基因的情况下在氧诱导的培养休克时衰老（6）。Myc也会导致缺乏DNA修复蛋白Myc的细胞衰老（7）。然而，与Cdk 2的缺失不同，Cdk 2的缺失不会增强Myc诱导的复制应激，这意味着这些蛋白质通过不同的途径抑制衰老。在MEFs中，Myc诱导的衰老在遗传上依赖于ARF-p53-p21（Clp 1）和p16（INK 4a）-pRb通路，p21（Clp 1）和p16（INK 4a）在Cdk 2（-/-）细胞中被选择性诱导。因此，尽管对于细胞周期进程和发育来说是多余的（4，5，9 -12），但Cdk 2在抑制癌基因和/或应激诱导的衰老中具有独特的作用（1）。Cdk 2的药理学抑制在各种细胞类型中诱导Myc依赖性衰老，包括p53缺失的人癌细胞系。我们的数据保证重新评估Cdk 2作为Myc或Wnt驱动的肿瘤的治疗靶点。
Activated oncogenes induce compensatory tumour-suppressive responses, such as cellular senescence or apoptosis, but the signals determining the main outcome remain to be fully understood(1,2). Here, we uncover a role for Cdk2 (cyclin-dependent kinase 2) in suppressing Myc-induced senescence. Short-term activation of Myc promoted cell-cycle progression(3) in either wild-type or Cdk2 knockout(4,5) mouse embryo fibroblasts (MEFs). In the knockout MEFs, however, the initial hyper-proliferative response was followed by cellular senescence. Loss of Cdk2 also caused sensitization to Myc-induced senescence in pancreatic beta-cells or splenic B-cells in vivo, correlating with delayed lymphoma onset in the latter. Cdk2(-/-) MEFs also senesced upon ectopic Wnt signalling or, without an oncogene, upon oxygen-induced culture shock(6). Myc also causes senescence in cells lacking the DNA repair protein Wrn(7). However, unlike loss of Wrn(8), loss of Cdk2 did not enhance Myc-induced replication stress, implying that these proteins suppress senescence through different routes. In MEFs, Myc-induced senescence was genetically dependent on the ARF-p53-p21(Clp1) and p16(INK4a)-pRb pathways, p21(Clp1) and p16(INK4a) being selectively induced in Cdk2(-/-) cells. Thus, although redundant for cell-cycle progression and development(4,5,9-12), Cdk2 has a unique role in suppressing oncogene- and/or stress-induced senescence(1). Pharmacological inhibition of Cdk2 induced Myc-dependent senescence in various cell types, including a p53-null human cancer cell line. Our data warrant re-assessment of Cdk2 as a therapeutic target in Myc- or Wnt-driven tumours.